Process

ABSTRACT

The novel process of the invention for the preparation of a compound of the formula ##STR1##

PRIOR APPLICATION

This application is a division of U.S. patent application Ser. No.177,158 filed Jan. 4, 1994 now U.S. Pat. No. 5,391,732.

OBJECTS OF THE INVENTION

It is an object of the invention to provide a novel process for thepreparation of a compound of formula I and novel intermediates.

This and other objects and advantages of the invention will becomeobvious from the following detailed description.

THE INVENTION

The novel process of the invention for the preparation of a compound ofthe formula ##STR2## wherein R₁ is selected from the group consisting ofalkyl, alkenyl, alkynyl and alkylthio of up to 10 carbon atoms andcycloalkyl of 3 to 7 carbon atoms, all optionally substituted, R₂ and R₃are individually selected from the group consisting of:

a) hydrogen, halogen --OH, --SH, acyl of an organic carboxylic acid of 1to 7 carbon atoms, --NO₂, --CN, free, salified or esterified carboxy and--PO₃ (R)₂,

b) --(CH₂)_(m1) --S(O)_(m2) --X--R₁₀,

c) alkyl, alkenyl, alkoxy and optionally oxidized alkylthio of up to 6carbon atoms optionally interrupted by at least one --O--, --S-- ornitrogen and optionally substituted,

d) optionally substituted phenyl, benzoyl and optionally oxidizedphenylthio,

e) ##STR3## f) --S--S--R₁₂, R is hydrogen or optionally substitutedalkyl or phenyl, m₁ is an integer from 0 to 4, m₂ is an integer from 0to 2, X is selected from the group consisting of a single bond, --NH--,--NHCO--, --NH--COO--, --N═CH--N--R₁₃ and --NHCONH--, R₁₀ and R₁₃ areindividually selected from the group consisting of hydrogen, alkyl andalkenyl of up to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms,optionally substituted phenyl and benzyl, pyridyl, nitropyridyl,pyrimidyl, tetrazolyl, diazolyl, piperidinyl, alkylpiperidinyl,thiazolyl, alkylthiazolyl, tetrahydrofuranyl andmethyltetrahydrofuranyl; R₆ and R₇ or R₈ and R₉ are individuallyselected from the group consisting of hydrogen, amino acids, optionallysubstituted alkyl and alkenyl of up to 6 carbon atoms, optionallysubstituted phenyl, benzyl and phenethyl and --(CH₂)_(m1) --S(O)_(m2)--X--R₁₀ or R₆ and R₇ or R₈ and R₉ taken together with the nitrogen towhich they are attached form a monocyclic ring of 5 to 7 ring members orcondensed rings of 8 to 14 ring members, both optionally containing atleast one heteratom of the group consisting of --O--, --S-- and nitrogenand optionally substituted with at least one member of the groupconsisting of halogen, --OH, --NO₂, alkyl and alkoxy of 1 to 6 carbonatoms, --NH₂, mono and dialkylamino of 1 to 6 carbon atoms and phenyl orR₈ and R₉ are individually acyl of an organic carboxylic acid of 1 to 6carbon atoms or one of R₈ and R₉ is carbamoyl, alkoxylcarbonyl orbenzyloxycarbonyl or R₈ and R₉ together with the nitrogen formphthalimido or succinimido, R₁₂ has the definitions of R₂ and R₃ exceptfor amino or alkoxy with the proviso that at least one of R₂ and R₃ isan optionally substituted alkoxy or --(CH₂)_(m1) --S(O)_(m2) --X--R₁₀,R₄ is selected from the groups consisting of --(CH₂)_(m1) --S(O)_(m2)--X--R₁₀ as defined above, halogen, nitro, --(CH₂)_(m1) --COOR₁₄,--(CH₂)_(m1) --CONHR₁₄, --(CH₂)_(m1) --CN, in which ml has the meaningabove, --SO₂ --NH--SO₂ --R₁₄, --NH--SO₂ --R₁₄, --PO₃ R₁₄, --NH--SO₂ CF₃and ##STR4## --(CH₂)_(m1) --SO₃ R₁₄, --CO--NH--OR₁₄, --CO--NH--NH--SO₂--CF₃, --CO--NH--SO₂ --R₁₄, --CH₂ SO₂ NHCO--R₁₄, --CH₂ CONH--SO₂ R₁₄,--NHSO₂ NHCO--R₁₄, --NHCONHSO₂ --R₁₄, --CONHSO₂ NR₁₄ R₁₅, --SO₂ NHCONR₁₄R₁₅, --SO₂ N(R₁₄)OR₁₅, --SO₂ NHPO(R₁₄)₂, --CONHPO(R₁₄)₂, --SO₂ NHCN,--SO₂ NHCOR₁₄, --SO₂ NHSO₂ NR₁₄ R₁₅, --SO₂ NHSO₂ N(CH₂ CH₂)₂ Y, --NHSO₂NHSO₂ R₁₄, --NHSO₂ NHPO(R₁₄)₂, --NR₁₄ COCO₂ H, --SO₂ NHCO₂ R₁₄, in whichR₁₃ has the definition above and R₁₄ and R₁₅ are individually selectedfrom the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms,optionally substituted cycloalkyl of 3 to 6 carbon atoms, and Y isoxygen or sulfur, all the alkyl, alkenyl, cycloalkyl, alkylthio,phenylthio, alkoxy, phenyl, benzyl radicals being optionally substitutedby at least one member of the group consisting of halogen, hydroxyl,nitro, alkyl, alkenyl and alkoxy of up to 4 carbon atoms,trifluoromethyl, cyano, amino, mono and dialkylamino, free, salified oresterified carboxy, haloalkyl, alkylthio, haloalkylthio, haloalkoxy,phenyl, pyridyl, benzyl, phenethyl, benzoyl, phenoxy, benzyloxy,phenylthio, carbamoyl, acyl, acyloxy and tetrazolyl, the products offormula I being in all possible racemic, enantiomeric anddiastereoismoeric isomer forms, as well as the addition salts withmineral and organic acids or with mineral and organic bases of the saidproducts of formula I comprises reacting a compound of the formula##STR5## in which R'₁, R'₂ and R'₃ have the meanings above for R₁, R₂and R₃ respectively and in which the optional reactive functions areoptionally protected with a compound of the formula: ##STR6## in whichHal is halogen, B is boron and X₁ and X₂ are such that: either X₁ and X₂are individually selected from the group consisting of hydroxyl, alkyland alkoxy of 1 to 6 carbon atoms, phenyl and phenoxy, or X₁ with X₂form with the boron atom to which they are linked a ring selected fromthe group consisting of ##STR7## X₃ is hydrogen or alkyl of 1 to 4carbon atoms to obtain a product of the formula ##STR8## in which R'₁,R'₂, R'₃, X₁, X₂ and B have the meanings above, reacting the latter witha product of the formula ##STR9## in which X₄ is halogen, alkoxy,triflate or --O--SO₂ F and R'₄ has the meaning above for R₄ in which theoptional reactive functions are optionally protected to obtain a productof the formula ##STR10## optionally subjecting the latter to one or moreof the following reactions in any order:

a) an elimination reaction of the protective groups which can be carriedby the protected reactive functions,

b) a salification reaction with a mineral or organic acid or with abase,

c) an esterification reaction of the acid function,

d) a saponification reaction of the ester function,

e) a conversion reaction of the cyano function into an acid function,

f) a reduction reaction of the carboxy function into an alcoholfunction,

g) a conversion reaction of the alkoxy function into the hydroxylfunction,

h) an oxidation reaction of the group containing a sulfur atom into acorresponding sulfoxide or sulfone function,

i) a conversion reaction of the sulfoxide or sulfone function into acorresponding sulfoximine function,

j) a conversion reaction of the nitrile into tetrazole,

k) a resolution reaction of the racemic forms into resolved products,

l) a conversion reaction of the carboxy into carbamoyl,

m) a conversion reaction of the carbamoyl into nitrile,

said products of formula I thus obtained being in all the possibleracemic, enantiomeric and diastereoisomeric isomer forms.

In --(CH₂)_(m1) --S(O)_(m2) --X--R₁₀, when m¹ is other than 0,--(CH₂)_(m1) -- is alkylene such as methylene, ethylene, n-propylene orn-butylene and preferably when m is 0, 1 or 2, --(CH₂)_(m1) ismethylene, ethylene or a single bond. --S(O)_(m2) --X--R₁₀ moiety may bein a non-exhaustive manner selected from the group consisting of: --SO₂--NH₂, --SO₂ --NH--CH₃, --SO₂ --NH--CF₃, --SO₂ --NH--C₆ H₅, --SO₂--NH--CH₂ --C₆ H₅, --CH₂ --SO₂ --NH₂, --CH₂ --SO₂ --NH--C₆ H₅, --SO₂--NH--CO--NH--CH₃, --SO₂ --NH--CO--NH--C₆ H₅, --SO₂ --NH--CO--NH--CF₃,--SO₂ --NH--CO--NH--CH₂ --C₆ H₅, --SO₂ --NH--CO--NH--D in which D ispyridine or pyrimidine, ##STR11## --SO₂ --NH--CO--NH--CH₂ --CH₂ --CH₃,--SO₂ --NH--CO--NH--CH═CH--CH₃, ##STR12## in which A and B are chosenfrom hydrogen, phenyl, pyridyl and pyrimidyl, ##STR13##

In the products of formula I and in what follows: the alkyl preferablydesignates methyl, ethyl, propyl, isopropyl, butyl isobutyl, sec.-butyland tert-butyl but can also be pentyl or hexyl and particularlyisopentyl and isohexyl. The term alkenyl preferably designates vinyl,allyl, 1-propenyl, butenyl and particularly 1-butenyl or pentenyl. Theterm alkynyl preferably designates ethynyl, propynyl and linear orbranched butynyl.

Among the alkyls interrupted by one or more heteroatoms, there aremethoxymethyl, methoxyethoxymethyl, propylthiopropyl, propyloxypropyl,propylthioethyl, methylthiomethyl. Halogen preferably designateschlorine or bromine, but can also be fluorine or iodine. The term alkoxypreferably designates methoxy, ethoxy, propoxy or isopropoxy, but canalso be n- or secondary or tertiary butoxy.

The acyl preferably is derived from an organic carboxylic acid of 1 to 6carbon atoms such as formyl, acetyl, propionyl, butyryl or benzoyl, butalso pentanoyl, hexanoyl, acryloxyl, crotonoyl or carbamoyl. The aminosubstituted by one or two alkyls preferably designates groups in whichthe alkyl is chosen from the alkyls defined above such as for monoalkylamino, methylamino or ethylamino, or for dialkylamino dimethylamino ormethylethylamino. Acyloxy designates an acyl with the values indicatedabove and preferably formyloxy, acetyloxy, propionyloxy, butyryloxy orbenzoyloxy. Cycloalkyl preferably designates cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl.

The monocyclic and condensed rings designate saturated or unsaturatedrings. Examples of saturated monocyclic are pyrrolidinyl,imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholinyl,thio-morpholinyl, azepinyl, or unsaturated monocycles such as: pyrannyl,pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, thiazolyl, thiadiazolyl, oxazolyl, furazannyl, pyrrolinylsuch as delta 2-pyrrolinyl, imidazolinyl such as delta 2-imidazolinyl,pyrazolinyl such as delta 3-pyrazolinyl as well as the position isomersof the heteratom or heteroatoms which these groups can contain such asisothiazolyl or isoxazolyl.

The condensed rings may be saturated such as 1-oxa spiro [4,5]decyl,tetrahydropyran-2-spirocyclohexyl, cyclohexanespiro-2'-(tetrahydrofuran)or 1, 10-diaza anthr-4-yl, or unsaturated such as benzothienyl,naphtho[2,3-b]thienyl, idenyl, indolizinyl, isoindolyl, 3H-indolyl,indolyl, indazolyl, purinyl, quinolizinyl, benzopyrrolyl,benzimidazolyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl,quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl,beta-carbolinyl, acridinyl, phenazinyl, indolinyl, isoindolinyl and alsocondensed polycyclic systems constituted by heterocyclic monocycles asdefined above such as furo[2,3-b]pyrrole or thieno[2,3-b]furan.

Haloalkyl is the alkyl as defined above and is substituted by one ormore halogens as defined above for example bromoethyl, trifluoromethyl,trifluoroethyl or pentafluoroethyl. Alkylthio preferably is the alkyl asdefined above, for example methylthio or ethylthio and haloalkylthiopreferably is the alkyl as defined above and is substituted by one ormore halogens as defined above, for example bromoethylthio,trifluoromethylthio, trifluoroethylthio or pentafluoroethylthio.Haloalkoxythio preferably is the alkoxy as defined above and issubstituted by one or more halogens as defined above, for examplebromoethoxy, trifluoromethoxy, trifluoroethoxy or pentafluoro-ethoxy.

Carbamoyl also designates carbamoyl substituted by a lower N-monoalkylcarbamoyl such as N-methylcarbamoyl, N-ethylcarbamoyl, a lowerN,N-dialkyl carbamoyl such as N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl; and N-(lower hydroxyalkyl) carbamoyl such asN-(hydroxymethyl) carbamoyl, N-(hydroxyethyl) carbamoyl, a lowercarbamoylalkyl such as carbamoylmethyl and carbamoylethyl. Phenylsubstituted by an alkythio is for example benzylthio.

In the products of formula I and in what follows, the alkyl, alkenyl,cycloalkyl and phenyl which can be represented by or carried by R₁, R₂,R₃ and R₄ can take the values defined above and may or may not besubstituted by one or more identical or different substituents asdefined above. Therefore, R₂ and R₃ can, for example, be alkylthio,phenylthio, alkylsulfinyl phenylsulfinyl, alkylsufonyl or arylsufonylbut also cycloalkylthio such as cyclohexylthio. Alkylthio, alkylsulfinyland alkylsulfonyl may be linear or branched alkyl as indicated above forthe alkyl. Examples are methylthio, hydroxymethylthio, ethylthio,aminoethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl,ethylsulfonyl, propylthio, isopropylthio, butylthio, sec-butylthio,tert-butylthio, isopentylthio or isohexylthio or those in which the thiois oxidized into the sulfinyl or sulfonyl.

Depending on the values of m1, m2 and R₁₀ in --(CH₂)_(m1) --S(O)_(m2)--X--R₁₀, R₂ and R₃ can also be phenylthio, pyridylthio orpyrimidylthio, imidazolylthio, N-methylimidazolylthio as well as thosein which the thio is oxidized into the sulfinyl or sulfonyl such asphenylsulfinyl or phenylsulfonyl.

As examples of substituted alkyls, there are those substituted by one ormore phenyl for example, benzyl, diphenylmethyl and triphenylmethyl, andthose substituted by pyridyl, for example pyridylmethyl, it beingunderstood that in the non-exhaustive list of examples as mentionedabove, the alkyl can also just as equally be ethyl, propyl or butyl suchas phenethyl.

Examples of substituted alkenyl are those substituted with at least onephenyl or pyridyl, as indicated in the examples given above in which thealkyl is replaced by an alkenyl for example phenylvinyl or phenylallyl.

The carbamoyl and amino radicals mentioned above in particular:##STR14## designate groups in which two identical or different groupsare linked to the nitrogen atom selected from the group consisting ofhydrogen to obtain the amino; the alkyl as defined above to obtain themonoalkyl- or dialkylamino in which the linear or branched alkyl have 1to 6 carbon atoms and particularly methyl, ethyl, isopropyl,methoxymethyl, methoxyethyl or ethoxyethyl; phenyl, benzyl, phenethyloptionally substituted to obtain the phenylamino or benzylamino.

Among the substituted carbamoyl, there are lower N-monoalkyl carbamoyl,for example, N-methylcarbamoyl, N-ethylcarbamoyl; the lower N,N-dialkylcarbamoyl, for example, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl; theN-(lower hydroxyalkyl) carbamoyl, for example, N-(hydroxymethyl)carbamoyl, N-(hydroxyethyl) carbamoyl; the lower carbamoylalkyl, forexample carbamoylmethyl, carbamoylethyl; phenylcarbamoyl;pyridylcarbamoyl; benzylcarbamoyl; N-methyl N-phenylcarbamoyl;pyridylmethyl-carbamoyl.

The expression amino acid is preferably a remainder derived from one ofthe natural amino acids such as glycine, alanine, valine, leucine,isoleucine, phenylalanine and particularly proline or one of the othernatural amino acids known to one skilled in the art.

Among the --(CH₂)_(m1) --X--R₁₀ which can be represented by R₆, R₇, R₈or R₉ are --NH--SO₂ --CH₃, --NH--SO₂ --C₆ H₅, --NH--SO₂ --CF₃, --NH--CH₂--SO₂ --NH--C₆ H₅, --CO--NH--SO₂ --C₂ H₅, --CO--NH--SO₂ --CH₃,--CO--NH--SO₂ --CH₂ --C₆ H₅. The heterocycle which can be formed with R₆and R₇ or R₈ and R₉ is preferably saturated.

It can be optionally substituted by the substituents already mentionedpreviously and particularly by one or more members selected from thegroup consisting of chlorine, fluorine, methyl, ethyl, isopropyl,tert-butyl, methoxy, ethoxy, propoxy, benzoyl, methoxycarbonyl,ethoxycarbonyl. For example methylpiperazinyl, ethylpiperazinyl,propylpiperazinyl, phenyl-piperazinyl or benzylpiperazinyl. In theselast two, the phenyl and benzyl can be substituted as indicatedpreviously for example chlorophenyl or trifluorophenyl.

The acyl of R₈ and R₉ can be chosen from acetyl, propionyl, butyryl,pentanoyl and carbamoyl. When R₈ or R₉ is alkoxy-carbonyl, this ispreferably tert-butyloxycarbonyl.

The carboxy of the products of formula I can be salified or esterifiedby various groups known to one skilled in the art among which there canbe mentioned, for example: among the salification compounds, mineralbases such as sodium, potassium, lithium, calcium, magnesium or ammoniumsalt or organic bases such as methylamine, propylamine, trimethylamine,diethylamine, triethylamine, N, N-dimethylthanolamine, tris(hydroxymethyl) amino methane, ethanolamine, pyridine, picoline,dicyclo-hexylamine, morpholine, benzylamine, procaine, lysine, arginine,histidine, N-methylglucamine.

Among the esterification compounds are, alkyl to form alkoxy carbonylgroups such as methoxycarbonyl, ethoxycarbonyl, tertbutoxycarbonyl orbenzyloxycarbonyl which alkyls may be substituted by members selectedfrom the group consisting of halogen, hydroxyl, alkoxy, acyl, acyloxy,alkylthio, amino or aryl such as chloromethyl, hydroxypropyl,methoxymethyl, propionyloxymethyl, methylthiomethyl, dimethylaminoethyl,benzyl or phenethyl.

The addition salts with mineral or organic acids of the products offormula I can be the salts formed with the following acids: hydrochloricacid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid,phosphoric acid, propionic acid, acetic acid, formic acid, benzoic acid,maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid,oxalic acid, glyoxylic acid, aspartic acid, ascorbic acid,alkylmonosulphonic acid such as methanesulfonic acid, ethanesulfonicacid, propanesulfonic acid, alkyldisulfonic acid such asmethanedisulfonic acid, α,β-ethanedisulfonic acid, arylmonosulfonic acidsuch as benzenesulfonic acid and aryldisulfonic acid.

When R₂ and R₃ both are individually an optionally oxidized sulfurousalkylthio or phenylthio, the preferred products of the invention areparticularly the products of formula I in which these sulphurous groupshave the same degree of oxidation.

Among the preferred compounds of formula I are those wherein one of R₂and R₃ is an optionally oxidized sulfur group as defined above and theother is alkyl, alkoxy, free, salified or esterifed carboxy oroptionally substituted phenyl, preferably R₂.

R₂ and/or R₃ can be notably alkylthio or alkenylthio optionallysubstituted by one or more formyl; hydroxyl; alkoxy; acyloxy; free,salified or esterified carboxy; amino; substituted amino; carbamoyl;substituted carbamoyl; alkylthio; phenylthio; pyridinyl; pyrimidinyl;phenyl.

Among the substituents which can be carried by R₂ and R₃ amino andcarbamoyl can in particular be substituted by one or two alkyl and aminoacids mentioned above.

The substituted amino and carbamoyl which can be carried by R₂ and R₃can also form a heterocycle such as those mentioned above.

Also R₂ and R₃ can be notably alkylthio substituted by one or morehalogen atoms such as chlorine and fluorine. For example the followingcan be mentioned: --S--CF₃ ; --S--CHF₂ ; --S--CH₂ F; --S--CF₂ --CHF₂ ;--S--CF₂ --CHFCl.

R₂ and R₃ can thus represent: ##STR15## --SO₃ H; --S--CH₃ ;--S--(CH₂)_(n1) --S--(CH₂)_(n2) --X₄ ; --S--(CH₂)_(n) --X₄ ;--S--(CH₂)_(n1) --NH--(CH₂)_(n2) --X₄ ; --S--CH═CH--(CH₂)_(n) --X₄ ;--S--(CH₂)_(n1) --CH═CH--(CH₂)_(n2) --X₄ ; in which X₄ is H, OH,cyclohexyl, pyridyl, phenyl, CHO, COOH, NH₂ or ##STR16## and n, n₁ andn₂ individually represent 0, 1 or 2.

R₂ and R₃ can be particularly --COOH; --CO₂ X₅ ; --SX₅ ; --NH₂ ;--C.tbd.N; --OMe; --OEt; --CH═CH--COOH; tetrazolyl; ##STR17## in alltheir isomer, cis-trans isomer forms, ##STR18## --NH--CH₂ --COO--X₅--NH--COO--X₅ X₅ is alkyl or aryl.

R₂ and R₃ can preferably be ##STR19##

The products of formula I represent in particular products in which R₂and R₃ have the meanings indicated above and quite particularly productsin which R₂ is an optionally substituted alkylthio as defined above oran alkoxy such as methoxy and R₃ is a free, salified or esterifiedcarboxy or an amidified carboxy such as --COOH, --COO methyl,--COO-ethyl, --CONH₂ or ##STR20##

Among the preferred values of R₄ are cyano, --(CH₂)_(m1) --SO₂ --X--R₁₀as defined above and more particularly --SO₂ --NH--CO--NH--CH₂ --CH═CH₂,--SO₂ --NH--CO--NH--CH₂ --CH₂ --CH₃, --SO₂ --N⁻ --CO--NH--CH₂ --CH₂--CH₃, K⁺ ##STR21##

The invention is preferably the above process for the preparation ofproducts of the formula ##STR22## in which:

R_(1a) is alkyl or alkenyl of up to 4 carbon atoms,

R_(2a) and R_(3a) are individually chosen from:

a) hydrogen, mercapto; formyl; free, salified or esterified carboxy;halogen; hydroxyl; cyano; nitro; acyl;

b) alkyl, alkenyl, alkoxy, alkylthio in which the sulfur atom isoptionally mono- or dioxidized having up to 6 carbon atoms, phenyl,benzoyl, phenylthio in which the sulfur atom is optionally mono- ordioxidized, all being optionally substituted by at least one member ofthe group consisting of halogen, hydroxyl, trifluoromethyl, cyano,nitro, formyl, alkyl and alkoxy of 1 to 4 carbon atoms, phenyl and free,salified or esterified carboxy, ##STR23## in which:

either R_(6a), R_(7a), R_(8a) and R_(9a) are individually chosen fromhydrogen, amino acids, alkyl of 1 to 6 carbon atoms, phenyl, benzyl,phenethyl or R_(6a) and R_(7a) and R_(8a) and R_(9a) form respectivelywith the nitrogen atom to which they are linked a heterocyclic selectedfrom the group consisting of imidazolyl, pyrrolyl, pyrrolinyl,pyrrolidinyl, pyridyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl,piperazinyl, phenylpiperazinyl, piperidyl, oxazolyl, morpholinyl andthiomorpholinyl, azepinyl, indolyl, optionally substituted by at leastone member of the group consisting of halogen, hydroxyl, nitro, alkyland alkoxy of 1 to 6 carbon atoms and phenyl, R_(4a) is cyano, free,salified or esterified carboxy, --(CH₂)_(p) --X_(a) --R_(10a) in which pis 0 or 1, X_(a) is --NH--, --NH--CO--, --NH--CO--O--,--N═CH--N--R_(13a), --NH--CO--NH-- or a single bond and R_(10a) andR_(13a) are individually selected from the group consisting of alkyl oralkenyl of up to 6 carbon atoms and optionally substituted, pyridyl,phenyl, benzyl, nitropyridyl, pyrimidyl, tetrazolyl, diazolyl,piperidinyl, alkylpiperidinyl, thiazolyl, alkylthiazolyl,tetrahydrofuranyl and methyltetrahydrofuranyl; the alkyl and alkenylbeing optionally substituted by at least one member of the groupconsisting of halogen, hydroxyl, nitro, alkyl, alkenyl and alkoxy of upto 4 carbon atoms, trifluoro-methyl, cyano, amino, mono- anddialkylamino, free, salified or esterified carboxy, phenyl andtetrazolyl; the said products of formula I_(a) being in all possibleracemic, enantiomeric and diastereoisomeric isomer forms, as well as theaddition salts with mineral and organic acids or with mineral andorganic bases of the said products of formula I_(a), characterized inthat for their preparation as defined above, products of formulae A, II,III and a reagent capable of introducing the R'₂ radical are used inwhich R'₁, R'₂, R'₃ and R'₄ have the values indicated above for R_(1a),R_(2a), R_(3a) and R_(4a) respectively in which the reactive functionsare optionally protected.

Another preferred process of the invention for the preparation ofcompounds of the formula ##STR24## in which:

R_(1b) is alkyl of up to 1 to 4 carbon atoms, R_(3b) is hydrogen,formyl, acyloxy, alkyl or alkoxy optionally substituted or carboxy free,salified or esterified by an alkyl, R_(2b) is optionally substitutedphenylthio, phenylsulfonyl, phenylsulfinyl, alkylthio, alkylsulfonyl oralkylsulfinyl such as in all those represented by R_(2b) and R_(3b),alkyl and alkoxy of 1 to 6 carbon atoms, and the phenyl is optionallysubstituted by one or more groups chosen from halogen, hydroxyl,trifluoromethyl, acyloxy, free salified or esterified carboxy, phenyl,pyridyl, tetrazolyl, alkyl and alkoxy of 1 to 4 carbon atoms optionallysubstituted by alkoxy of 1 to 4 carbon atoms, R_(4b) is cyano, free,salified or esterified carboxy, --SO₂ --X_(b) --R_(10b) in which X_(b)is --NH--, --NH--CO--, --NH--CO--O--, ##STR25## --NH--CO--NH-- or asingle bond and R_(10b) and R_(13b) are individually selected from thegroup consisting of hydrogen, methyl, ethyl, propyl, vinyl, allyl,pyridyl, phenyl, benzyl, nitropyridyl, pyrimidyl, tetrazolyl, diazolyl,piperidinyl, alkylpiperidinyl, thiazolyl, alkylthiazolyl,tetrahydrofuranyl and methyltetrahydrofuranyl, the said products offormula I_(b) being in all possible racemic, enantiomeric anddiastereoisomeric isomer forms, as well as the addition salts withmineral and organic acids or with mineral and organic bases of saidproducts of formula I_(b), characterized in that for their preparationas defined above, products of formulae A, II, III and a reagent capableof introducing R'₂ are used in which R'₁, R'₂, R'₃ and R'₄ have thevalues indicated above for R_(1b), R_(2b), R_(3b) and R_(4b)respectively in which the reactive functions are optionally protected.

A more particular subject of the invention is the process for thepreparation of products of the formula ##STR26## in which:

R_(1d) is alkyl of 1 to 4 carbon atoms, R_(3d) is selected from thegroup consisting of carboxy free, salified or esterified by alkyl of 1to 4 carbon atoms, formyl, acyloxy, alkyl of 1 to 4 carbon atomsoptionally substituted by hydroxyl, R_(2d) is selected from the groupconsisting of phenylthio, phenylsulfonyl, phenylsulfinyl, alkylthio,alkylsulfonyl or alkylsulfinyl, in which the alkyl has 1 to 4 carbonatoms, and R_(4d) is --SO₂ --NH₂, --SO₂ --NH--CO--O--R_(10d), --SO₂--N═CH--NR_(13d), or --SO₂ --NH--CO--NH--R_(10d) in which R_(10d) andR_(13d) are individually selected from the group consisting of hydrogen,methyl, ethyl, n-propyl and propenyl, the said products of formula I_(d)being in all possible racemic, enantiomeric and diastereoisomeric isomerforms, as well as the addition salts with mineral and organic acids orwith mineral and organic bases of said products of formula I_(d),characterized in that for their preparation as defined above, productsof formulae II, III and IV and a reagent capable of introducing the R'₂are used in which R'₁, R'₂, R'₃ and R'₄ have the values indicated abovefor R_(1d), R_(2d), R_(3d) and R_(4d) respectively in which the reactivefunctions are optionally protected.

In a preferred mode of the process, the compound of formula II with R'₁being alkyl of 1 to 4 carbon atoms, R'₃ is selected from the groupconsisting of free, salified or esterified carboxy with alkyl of 1 to 4carbon atoms formyl, acyloxy and alkyl of 1 to 4 carbon atoms optionallysubstituted with hydroxy and R'₂ is selected from the group consistingof phenylthio, phenylsulfonyl, phenylsulfinyl, alkylthio, alkylsulfonyland alkylsulfinyl of 1 to 4 alkyl carbon atoms and the protective groupsare optionally protected is reacted with a compound of formula V whereinR'₄ is selected from the group consisting of --SO₂ --NH₂, --SO₂--NH--CO--O--R_(10d), --SO₂ --N═CH--NR_(13d), or --SO₂--NH--CO--NH--R_(10d) in which R_(10d) and R_(13d) are individuallychosen from hydrogen, methyl, ethyl, n-propyl and propenyl, in which thereactive functions are optionally protected.

More preferably, the compound of formula II has R'₃ as alkoxy or free,salified or esterified carboxy and R'₂ is alkylthio or phenylthiooptionally oxidized in the form of the sulfoxide or sulfone, thesealkoxy, alkylthio and phenylthio being optionally substituted by atleast one member of the group consisting of halogen, alkyl and alkoxy of1 to 4 carbon atoms, trifluoromethyl, amino, mono or dialkylamino,cyano, acyl, acyloxy and phenyl.

The compounds of formula I preferred by the process are preferably

-2-butyl-1-[[2'-carboxy-(1,1'-biphenyl)-4-yl]-methyl]-4-(phenylthio)-1H-imidazole-5-carboxylicacid,

-2-butyl-1-[[2'-carboxy-(1,1'-biphenyl)-4-yl]-methyl]-4-(methylthio)-1H-imidazole-5-carboxylicacid,

-4'-[[2-butyl-4-(ethylthio)-5-(hydroxymethyl)-1H-imidazol-1-yl]-methyl]-(1,1'-biphenyl)-2-carboxylicacid,

-2-butyl-1-[[2'-carboxy-(1,1'-biphenyl)-4-yl]-methyl]-4-(ethylsulfonyl)-1H-imidazole-5-carboxylicacid,

-2-butyl-1-[[2'-carboxy-(1,1'-biphenyl)-4-yl]-methyl]-4-(ethylsulfinyl)-1H-imidazole-5-carboxylicacid,

-2-butyl-1-[[2'-carboxy-(1,1'-biphenyl)-4-yl]-methyl]-4-(ethylthio)-1H-imidazole-5-carboxylicacid,

-2-butyl-1-[[2'-carboxy-(1,1'-biphenyl)-4-yl]-methyl]-4-(phenylsulfonyl)-1H-imidazole-5-carboxylicacid,

-2-butyl-1-[[2'-carboxy-(1,1'-biphenyl)-4-yl]-methyl]-4-(phenylsulfinyl)-1H-imidazole-5-carboxylicacid,

-2-butyl-1-[[2'-tetrazolyl-(1,1'-biphenyl)-4-yl]-methyl]-4-(methylthio)-1H-imidazole-5-carboxylicacid,

-ethyl2-butyl-4-(methylthio)-1-[[2'-((((propylamino)-carbonyl)-amino)-sulfonyl)-(1,1'-biphenyl)-4-yl]-methyl]-1H-imidazole-5-carboxylate,

-2-butyl-4-(methylthio)-1-[[2'-((((propylamino)-carbonyl)-amino)-sulfonyl)-(1,1'-biphenyl)-4-yl]-methyl]-1H-imidazole-5-carboxylicacid,

-2-butyl-4-(methylthio)-1-[[2'-((((propylamino)-carbonyl)-amino)-sulfonyl)-(1,1'-biphenyl)-4-yl]-methyl]-1H-imidazole-5-carboxylicacid, -di-potassium salt,

Preferably, the compound of formula III is such that Hal is preferablybromine but can also be chlorine or iodine.

The reaction of the product of formula III with the product of formulaII can be carried out in a solvent such as dimethylformamide,tetrahydrofuran, acetone, acetonitrile, dimethylpropylurea,dimethoxyethane or dimethylsulfoxide at reflux of the solvent or atambient temperature, preferably with stirring. The reaction is carriedout in the presence of a base such as sodium or potassium hydride,sodium or potassium methylate, ethylate or tert-butylate, or preferably,sodium, potassium or caesium carbonate.

The reaction of the product of formula IV with the compound of formula Vas defined above in which X₄ is preferably bromine, iodine or chlorinecan be carried out in a solvent such as a mixture of toluene and ethanolor dimethylformamide in the presence of a weak base such as sodium,potassium or caesium bicarbonate, preferably in the presence of acatalyst such as tetrakis triphenylphosphine palladium or a mixture oftriphenylphosphine and palladium diacetate or also in tetrakistriphenylphosphine nickel.

As other catalysts, there can be mentioned nickel, Pd, Rh or Ptcomplexes and preferably complexes of palladium; bis(dibenzylideneacetone) Pd in the presence of PPh₃ ; tris(dibenzylidene acetone) Pd;trans-benzyl (chloro) bis(triphenylphosphine) palladium; Pd(OAc)₂ trisfuryl phosphine; Pd(OAc)₂ triphenyl phosphine; tetrakistriphenylphosphine palladium; 1,4 bis(diphenylphosphino) butane Pd, Cl,Br or OAc; 1,3 bis(diphenyl phosphino) propane Pd, Cl, Br or OAc; 1,2bis(diphenyl phosphino) ethane Pd, Cl, Br or OAc; 1,1 bis(diphenylphosphino) ferrocene Pd, Cl, Br, or OAc.

In the reaction of the product of formula IV with the product of formulaV, the solvents used are preferably degassed beforehand, for example bybubbling argon through them.

The various reactive functions that can be carried by certain compoundsof the reactions defined above can, if necessary, be protected. They canbe for example hydroxyl, acyl, free carboxy or also amino andmonoalkylamino which can be protected by appropriate protective groups.A list of the different protective groups which can be used will befound for example in the French Patent No. 2,499,995.

The following non-exhaustive list of examples of the protection of thereactive functions can be mentioned: the hydroxyl groups can beprotected for example by alkyl such as tert-butyl, trimethylsilyl,tert-butyldimethylsilyl, methoxymethyl, tetrahydropyrannyl, benzyl oracetyl. The amino groups can be protected for example by acetyl, trityl,benzyl, tert-butoxycarbonyl, phthalimido or by others known in thechemistry of the peptides. Acyl groups such as formyl can be protectedin the form of cyclic or non-cyclic ketals such as dimethyl- ordiethylketal or ethylene dioxyketal and the acid functions of theproducts can be optionally amidified by a primary or secondary amine forexample in methylene chloride in the presence of1-ethyl-3-(dimethylaminopropyl)-carbodiimide hydrochloride at ambienttemperature. The acid functions can be protected for example in the formof esters formed with easily-cleavable esters such as benzyl orter-butyl esters or esters known in the chemistry of the peptides.

Depending upon the values of R'₁, R'₂, R'₃ and R'₄, the products offormula I' as defined above constitute or do not constitute products offormula I.

The reactions to which the products of formula I' as defined above canbe optionally subjected, can be carried out, for example, as indicatedbelow to obtain the compounds of formula I.

The elimination of the protective groups such as those indicated abovecan be carried out under the usual conditions known to one skilled inthe art, particularly by an acid hydrolysis carried out with an acidsuch as hydrochloric acid, benzene sulfonic acid or para-toluenesulfonic acid, formic acid or trifluoroacetic acid or also by catalytichydrogenation. The phthalimido group can be eliminated with hydrazine.

The products described above can, if desired, be subjected tosalification reactions for example with a mineral or organic acidaccording to the usual methods known to one skilled in the art. Theproducts described above can, if desired, be subjected, on the optionalcarboxy functions, to salification reactions with a mineral or organicbase or esterification reactions. These esterification and salificationreactions can be carried out according to the usual methods known to oneskilled in the art.

The optional conversions of the ester functions into the acid functionof the products described above can be, if desired, carried out underthe usual conditions known to one skilled in the art, particularlyalkaline or acid hydrolysis for example with sodium hydroxide orpotassium hydroxide in an alcoholic medium such as in methanol or withhydrochloric acid or sulfuric acid.

The optional cyano functions of the products can be, if desired,converted into an acid function by the usual conditions known to oneskilled in the art, for example by a double hydrolysis carried out in anacid medium such as in a sulfuric acid, glacial acetic acid and watermixture, these three compounds preferably being in equal proportions, orin a sodium hydroxide, ethanol and water mixture under reflux.

The optional free or esterified carboxy functions of the products canbe, if desired, reduced into an alcohol function by methods known to oneskilled in the art. For the esterified carboxy functions, lithiumaluminium hydride can be used in a solvent such as tetrahydrofuran ordioxane or ethyl ether. For the free carboxy functions, boron hydridecan be used.

The optional alkoxy functions such as methoxy of the products can be, ifdesired, converted into a hydroxyl function under the usual conditionsknown to one skilled in the art, for example with boron tribromide in asolvent such as methylene chloride, with pyridine hydrobromide orhydrochloride or with hydrobromic acid or hydrochloric acid in water orwith acetic acid under reflux.

The optional groups containing a sulfur atom of the products can be, ifdesired, converted into the corresponding sulfoxide or sulfone functionunder the usual conditions known to one skilled in the art such as bymeans of peracids such as peracetic acid or methachloroperbenzoic acidor with ozone, oxone, sodium periodate in a solvent such as methylenechloride or dioxane at ambient temperature.

The sulfoxide function can be obtained with an equimolar mixture of theproduct containing an alkylthio or arylthio and of the reagent such as aperacid. The sulfone function can be obtained with a mixture of theproduct containing an alkylthio or arylthio with an excess of reagentsuch as a peracid.

The optional alcohol function of the products can be, if desired,converted into the aldehyde or acid function by oxidation under theusual conditions known to one skilled in the art such as by the actionof manganese oxide to obtain aldehydes or Jones reagent to obtain acids.

The optional nitrile functions of the products can be, if desired,converted into tetrazole in the usual conditions known to one skilled inthe art such as by the cycloadditon of a metal azide such as atrialkyltin azide on the nitrile function as indicated in the methoddescribed in KOZIMA et al, J. Organometallic Chemistry, Vol. 33, p. 337,(1971).

The optional optically active forms of the products of formula I can beprepared by resolution of the racemics according to the usual methodsknown to one skilled in the art. The conversion reactions of the formylinto the carbamoyl and of the carbamoyl into the nitrile are carried outaccording to the usual conditions known to one skilled in the art.

The products of formula I are known and are described in European PatentApplication No. 0,465,368 and No. 0,503,162. The products of formula Iprepared by the process as defined above, as well as their additionsalts with acids, have useful pharmacological properities. They areendowed with antagonistic properties for the angiotensin II receptor andare particularly inhibitors of the effects of angiotensin II, especiallyof the vasoconstrictive effect and also of the trophic effect at thelevel of the myocytes.

These properties justify the use in therapeutics of the products offormula I prepared according to the process as defined above asmedicaments, and are useful in the treatment of arterial hypertension,cardiac insufficiencies, renal insufficiencies and in the prevention ofthe post-angioplastic recurrence of stenosis. They can also be used inthe treatment of certain gastrointestinal, gynaecological disorders andparticularly for a relaxing effect at the level of the uterus.

The compositions can be administered orally, rectally, parenterally orlocally as a topical application on the skin and mucous membranes. Thecompositions can be solid or liquid and in the forms of tablets,dragees, capsules, granules, suppositories, injectable preparations,ointments, creams, gels and aerosol preparations prepared by the usualmethods. The active ingredient can be incorporated with excipientsusually employed in these pharmaceutical compositions such as talc, gumarabic, lactose, starch, magnesium stearate, cocoa butter, aqueous ornon-aqueous vehicles, fatty substances of animal or vegetable origin,paraffin derivatives, glycols, various wetting, dispersing oremulsifying agents, preservatives.

The usual dose, variable according to the product used, the patienttreated and the illness in question, can be from 1 to 100 mg per day inan adult, by oral route.

Some of the starting products of formula II are known and can beprepared as indicated in European Patent EP 168,950. The startingproducts of formula II can be prepared by reacting a compound of theformula ##STR27## in which R'₂ has the the meaning above with a reducingagent to obtain a corresponding amine of the formula ##STR28## in whichR'₂ has the above meaning, reacting the latter with a compound of theformula ##STR29## in which R'₁ has the meaning above, and Hal is halogento obtain a product of the formula ##STR30## in which R'₁ and R'₂ havethe above meanings, reacting the latter with the compound of the formula

    R'.sub.3 --YH                                              II.sub.e

in which R'₃ has the meaning above, and Y is sulfur or oxygen to obtaina product of the formula ##STR31## in which R'₁, R'₂, R'₃ and Y have theabove meanings, subjecting the latter to a cyclization reaction toobtain a product of formula II which is optionally subjected to one ormore of the following reactions, in any order:

a) an elimination reaction of the protective groups which can be carriedby the protected reactive functions,

b) a salification reaction with a mineral or organic acid or with a baseto obtain the corresponding salt,

c) an esterification reaction of the acid function,

d) a saponification reaction of the ester function into an acidfunction,

e) a conversion reaction of the cyano function into an acid function,

f) a reduction reaction of the carboxy function into an alcoholfunction,

g) a conversion reaction of the alkoxy function into a hydroxylfunction,

h) an oxidation reaction of the group containing a sulfur atom into acorresponding sulfoxide or sulfone function,

i) an oxidation reaction of the alcohol function into an aldehyde oracid function,

j) a conversion reaction of the nitrile function into tetrazole,

k) a resolution reaction of the racemic forms into resolved products,

l) a conversion reaction of the carboxy into the carbamoyl,

m) a conversion reaction of the carbamoyl into a nitrile, the saidproducts of formula II thus obtained being in all possible racemic,enantiomeric and diastereoisomeric isomer forms.

In the preferred conditions for implementing the invention, the aboveprocess is carried out in the following manner: the reduction of theoxime of formula II_(a) can be carried out by the usual methods known toone skilled in the art such as with an aluminium amalgam prepared underthe usual conditions such as by the action of mercury chloride onaluminium. The reaction is carried out in a solvent such astetrahydrofuran or toluene, preferably at a temperature of approximately50° C.

The addition of the product of formula II_(c) in which W is bromine orpreferably chlorine on the amine of formula II_(b) can be carried out bymethods known to one skilled in the art, for example in the presence ofa base such as pyridine or triethylamine and the reaction is preferablycarried out at a temperature of approximately 0° C.

The compound of formula II_(d) can also be obtained by subjecting thecompound of formula II_(a) to a reduction and acylation reaction in thepresence of an anhydride such as acetic, butyric or valeric anhydride,by hydrogenation in the presence of palladium or zinc or of sodiumdithionite.

The addition of a sulfurated derivative of formula II_(e) on the amideof formula II_(d) is carried out, for example, by putting the amide offormula II_(d) in solution in a solvent such as an alcohol like ethanolor methanol, then the successive addition of a base such astriethylamine and of the compound of the formula II_(e) preferably withstirring at ambient temperature. The cyclization reaction of thecompound of formula II_(f) can be carried out in a solvent such asdichloromethane, dichloroethane or also chloroform and the reaction canbe carried out in the presence of phosphorous pentachloride dissolved indichloromethane at a temperature of approximately -78° C. in thepresence of a base such as pyridine or dimethylaminopyridine. Thereaction can be carried out with stirring at ambient temperature.

The product of formula II can be subjected to one or more of thereactions indicated above, these reactions being carried out under thesame conditions as those defined above for the products of formula I.The compound of formula II_(a) can be, for example,ethylisonitrosocyanoacetate which can be found in the form of a productmarketed by LANCASTER under the reference 8930.

The compound of formula III as defined above can be obtained by reactingthe compound in equilibrium in its trimer form of the formula ##STR32##in which:

B is defined as above and tol is tolyl with an appropriate alcohol suchas methanol, ethanol or butanol, or a diol such as propanediol,ethyleneglycol or dimethylpropanediol to obtain a compound of theformula ##STR33## in which B, X₁ and X₂ have the meanings above, andreacting the latter with a halogenation agent to obtain the product offormula III.

A modification of the process for the preparation of a compound offormula I comprises reacting a compound of formula IV with ahalogenation reagent as taught by Snyder et al, J. Ann. Chem. Soc., Vol.80, p. 835 (1958) to obtain a compound in equilibrium with its trimer ofthe formula ##STR34## in which B and tol have the meanings above, andHal is halogen, preferably bromine, and reacting the latter with thecompound of formula II to obtain the product of formula IV, then thesynthesis is continued as indicated above to obtain the product offormula I. Such reactions can be carried out under the conditionsindicated above and as described hereafter in the examples.

The preparation of the products of formula I can be effected by reactinga product of the formula ##STR35## in which R'₁, R'₂ and R'₃ have themeanings above with the product of formula III corresponding to theformula ##STR36## in which Hal and B have the meanings above to obtainthe product of the formula IV corresponding to the formula ##STR37## inwhich R'₁, R'₂, R'₃ and B have the meanings above and reacting thelatter with a compound of the formula ##STR38## in which Hal and R'₄have the meanings above. An example of such a preparation of a productof formula I is given in Example 1.

In the above process, the product of formula II can be reacted with theproduct of formula III corresponding to the formula ##STR39## in whichHal and B have the meanings above to obtain a product of formula IVcorresponding to the formula ##STR40## in which R'₁, R'₂, R'₃ and B havethe meanings above and reacting the latter with a product of formula V.An example of such a preparation of a product of formula I is given inExample 2.

The product of formula I can be subjected, if necessary and if desired,to various reactions to give other products of formula I, as indiciatedabove, notably to a saponification reaction. Similarly, the products offormula IV and as an example, the products of formulae IV_(a), IV_(b) orIV'_(b) can also be subjected to various reactions to give otherproducts of formula IV.

A subject of the present invention is also new industrial productsuseful as intermediate products which are necessary for the preparationfor the products of formula I which are the compounds of formulae IV andV as defined above.

Some products of formula III are also new and as such constitute asubject of the invention. These are

-2-iodobenzene-sulfonamide

-2-iodo-N-[(propylamino)-carbonyl]-benzene-sulfonamide

-2-[4-(bromomethyl)-phenyl]-5,5-dimethyl-1,3,2-dioxaborolane

-2-[4-(bromomethyl)-phenyl]-1,3,2-dioxaborolane

-ethyl1-[(4-boronophenyl)-methyl]-2-butyl-4-(methylthio)-1H-imidazole-5-carboxylate

-ethyl2-butyl-1-[4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-benzyl]-4-(methylthio)-1H-imidazole-5-carboxylate

-ethyl-2-butyl-1-[4-(1,3,2-dioxaborolan-2-yl)-benzyl-4-(methylthio)-1H-imidazole-5-carboxylate

-(T-4)-((4-((2-butyl-4-(methylthio)-5-(ethoxycarbonyl)-1H-imidazole-1-yl-((methyl)-phenyl)-((2,2'-methylimino)-bis-((ethanolato))-(2-)-N,O,O')-boron

-ethyl2-butyl-1-(4-(1,3,2-benzodioxaborol-2-yl)-benzyl-4-(methylthio)-1H-imidazole-5-carboxylate

-ethyl2-butyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxolaborolan-2-yl)-benzyl)-4-(methylthio)-1H-imidazole-5-carboxylate

-ethyl2-butyl-1-(4-(1,3,2-dioxolaborolan-2-yl)-benzyl-4-(methylthio)-1H-imidazole-5-carboxylate.

These products correspond to the following products 1 to 9: ##STR41## inwhich Z and W are individually hydrogen or alkyl notably methyl or ethyland the products 4, 6 and 9 as defined above are called 4a, 6a and 9arespectively when A is methyl and 4b, 6b and 9b respectively when Z ishydrogen. Preparation methods for the above compounds and some of theirhomologs are described in the examples.

In the following examples, there are described several preferredembodiments to illustrate the invention. However, it is to be understoodthat the invention is not intended to be limited to the specificembodiments.

Preparation 1

2-iodobenzene-sulfonamide (product 1)

3.5 g of α-aminobenzene-sulfonamide and 25 ml of 98% concentratedsulfuric acid were heated at 60° C. and 20 g of ice were added. Asolution of 1.45 g of sodium nitrite in 4 ml of water was added at 0°-5°C. and the mixture was stirred for 3 hours at a temperature below 10° C.Then a solution of 3.75 g of potassium iodide in 25 ml of water wasadded at 5°-10° C. and the reaction medium was stirred for 19 hours, 50ml of water were added followed by filtering, washing with water, thentaking up in 50 ml of ethyl acetate, washing with 0.2N solution ofsodium thiosulfate, then with water, and concentrating to obtain 4 g ofthe expected product melting at 197°-198° C.

IR (nujol) 3360, 3255, 1562 cm⁻¹ Mass spectrum M⁺ 283 NMR: CDCl₃ 5.17(sl, NH₂); 7.23 and 7.52 (td, aromatics, 2H); 8.08 and 8.20 (dd,aromatics, 2H)

Preparation 2

2-iodo-N-[(propylamino)-carbonyl]-1-benzene-sulfonamide (product 2)

4 g of iodobenzene-sulfonamide and 40 ml of acetone were mixed togetherand 3.92 g of potassium carbonate were added. The reaction was heated toreflux and 1.46 ml of n-propyl isocyanate were added. The medium wasmaintained at reflux for 2 hours, and after concentrating, 200 ml ofwater were added. Then, while cooling the reaction mixture toapproximately 0°-5° C., a 2N hydrochloric acid solution was added untila pH of 3 was obtained. After crystallizing from acetone-isopropylether, 4.9 g of the expected product melting at 211°-212° C. wereobtained.

IR (nujol) 3406, 3368, 1715, 1565, 1539 cm⁻¹ Mass spectrum M⁺ 368 NMR:CDCl₃ 0.82 (tJ=7.5, CH₃, 3H); 1.45 (m, CH₂, 2H); 3.14 (m, CH₂, 2H); 6.39(t, CONH, 1H); 7.29 (dt, J-1.5, aromatics); 7.54 (td, J-8.15,aromatics); 8.13 (m, aromatics); 7.59 (s, SO₂ NH, 1H).

The preparation of products 6a, 6b, 7, 8, 9a and 9b described in theexperimental part can be schematized as indicated hereafter. ##STR42##

Preparation 3

ethyl1-[(4-boronophenyl)-methyl]-2-butyl-4-(methylthio)-1H-imidazole-5-carboxylate(product 5)

Method 1

0.423 g of 4-bromomethyl-phenyl-boronic acid (prepared by the methoddescribed by Snyder et al., JACS, Vol. 80, p. 835 (1958)) were added toa mixture of 0.484 g of ethyl2-butyl-4-(methylthio)-1H-imidazole-5-carboxylate, 5 ml ofdimethylformamide and 0.552 g of potassium carbonate. After 48 hours ofstirring at ambient temperature, the reaction mixture was poured intoice-cooled water. The reaction medium was stirred for 15 minutesfollowed by filtering, washing with water and crystallization from amixture of cyclohexane and isopropyl ether to obtain 0.450 g of theexpected product.

Method 2

A solution of 11 g of 2-(4-bromomethyl-phenyl)-1,3,2-dioxaborolane in 66ml of dimethylformamide was added to a mixture of 9.44 g of ethyl2-butyl-4-(methylthio)-1H-imidazole-5-carboxylate, 62 ml of anhydrousdimethylformamide and 10.78 g of potassium carbonate. After 48 hours ofstirring at ambient temperature, the reaction mixture was poured intoice-cooled water and acidified to a pH of 2 with 2N hydrochloric acid.After filtering, washing with water and drying, 10.45 g of the expectedproduct melting at 169°-170° C. were obtained.

IR (nujol) 1693, 1610, 1555, 1513 cm⁻¹ Mass spectrum 1074 (trimer form)NMR: CDCl₃

A mixture of resolved monomer and trimer approx. 3/4-1/4 of 0.87 and0.86 signals (t, CH₃, 3H); 1.32 (m, CH₂, 2H); 1.30 (t, CO₂ CH₂ CH₃, 3H);1.64 (m, CH₂, 2H); 2.60 (m, CH₂, 2H); 2.61 and 2.63 (s, SCH₃, 3H) 4.25(q resolved, CO₂ CH₂ CH₃, 2H); 5.55 and 5.60 (s, N--CH₂ -Ph, 2H); 7.00and 7.68 (dl, aromatics, 2H); 7.11 and 8.12 (dl, aromatics, 2H); 4.93(m, wide approx. 0.2H, mobile).

Preparation 4

ethyl2-butyl-1-[4-(1,3,2-dioxaborolan-2-yl)-benzyl]-4-(methylthio)-1H-imidazole-5-carboxylate(product 6b)

A mixture of 1.292 g of ethyl1-[(4-boronophenyl)-methyl]-2-butyl-4-(methylthio)-1H-imidazole-5-carboxylateof Preparation 3, 25 ml of toluene and 0.710 ml of 1,3 propanediol wasstirred at reflux for 4 hours while eliminating the water formed. Afterevaporating to dryness under reduced pressure, the residue wascrystallized hot and cold from heptane, filtered and washed to obtain1.12 g of the desired product.

NMR: CDCl₃ (250 MHz) ppm 0.86 (t, 3H): CH₃ nBu; 1.30 (m, 2H)-1.60 (m,2H)-2.58 (t, 2H): the CH₂ nBu's; 1.28 (t, 3H)-4.23 (q, 2H): --COOEt;2.04 (m, 2H): O--CH₂ --CH₂ --CH₂ --O; 4.14 (t, 4H): --O--CH₂ --CH₂ --CH₂--O--; 2.58 (s, 3H): SCH₃ ; 5.52 (s, 2H): Ar--CH₂ -imidazole; 6.94 and7.68 (2D, 4H): aromatics.

Preparation 5

ethyl2-butyl-1-[4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-benzyl]-4-(methylthio)-1H-imidazole-5-carboxylate(product 6a)

Using the procedure of Preparation 4, 250 mg of ethyl1-[(4-boronophenyl)-methyl]-2-butyl-4-(methylthio)-1H-imidazole-5-carboxylateand 70 mg of 2,2'-dimethyl 1,3-propanediol were reacted to obtain 200 mgof the desired product.

Preparation 6

(T-4)-((4-((2-butyl-4-(methylthio)-5-(ethoxycarbonyl)-1H-imidazol-1-yl)-methyl)-phenyl)-((2,2'-(methylthio)-bis-(ethanolato))-(2-)-N,O,O')-boron(product 7)

Using the procedure of Preparation 4, 2 g of ethyl1-[(4-boronophenyl)-methyl]-2-butyl-4-(methylthio)-1H-imidazole-5-carboxylate,30 ml of cyclohexane and 10 ml of ethyl acetate and then after hotdissolution, 0.611 ml of N-methyldiethanolamine were reacted to obtainafter concentration, 2.17 g of the desired product.

NMR: CDCl₃ (250 MHz) ppm 0.85 (t, 3H): CH₃ nBu; 1.3 (t, 3H): CH₃ of--COOEt; 1.3 (m, 2H)-1.62 (q, 2H): CH₂ in position 3 and CH₂ in position2 nBu; 2.30 (s, 3H): --N⁺ --CH₃ ; 2.60 (s, 2H and t, 2H): S--CH₃ and CH₂in position 1 nBu; 2.98 and 3.20 (m, 4H): CH₂ --N⁺ ═; 4.15 (m, 4H): CH₂--B⁻ ═; 4.27 (q, 2H): CH₂ of COOEt; 5.50 (s, 2H): Ar--CH₂ -imidazole;6.9 and 7.5 (2d, 4H) aromatics.

Preparation 7

ethyl2-butyl-1-((4-1,3,2-benzodioxaborol-2-yl)-benzyl)-4-(methylthio)-1H-imidazole-5-carboxylate(product 8)

Using the procedure of Preparation 4, 1 g of ethyl1-[(4-boronophenyl)-methyl]-2-butyl-4-(methylthio)-1H-imidazole-5-carboxylateand 0.293 g of catechol were reacted to obtain the desired product.

NMR: CDCl₃ (200 MHz) ppm 0.87 (t, 3H): CH₃ of nBu; 1.35 (m, 2H): CH₂ inposition 3 of nBu; 1.65 (m, 2H): CH₂ in position 2 of nBu; 2.63 (t, 2H):CH₂ in position 1 of nBu; 1.30 (t, 3H): CH₃ of CO₂ Et; 4.25 (q, 2H): CH₂or CO₂ Et; 2.63 (s, 3H): SCH₃ ; 5.6 (s, 2H): CH₂ benzyl; 7.1 and 8.05(2d): aromatics; 7.15 and 7.3: catechol.

Preparation 8

ethyl2-butyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxolaborolan-2-yl)-benzyl-4-(methylthio)-1H-imidazole-5-carboxylate(product 9a)

Using the procedure of Preparation 4, 0.5 g of ethyl1-[(4-boronophenyl)-methyl]-2-butyl-4-(methylthio)-1H-imidazole-5-carboxylateand 0.189 g of pinacol were reacted to obtain 0.511 g of the desiredproduct.

NMR: CDCl₃ (250 MHz) ppm 0.87 (t, 3H): CH₃ of nBu; 1.33 (m, 2H): CH₂ inposition 3 of nBu; 1.63 (m, 2H): CH₂ in position 2 of nBu; 2.53 (t, 2H):CH₂ in position 1 of nBu; 1.33 (s, 12H): 4 CH₃ --C--; 1.23 (t, 3H): CO₂Et; 4.23 (q, 2H): CO₂ Et; 2.61 (s, 3H): S--CH₃ ; 5.53 (s): N--CH₂ --Ar;6.37 and 7.73 (2d, 4H): aromatics.

Preparation 9

ethyl2-butyl-1-(4-(1,3,2-dioxolaborolan-2-yl)-benzyl-4-(methylthio)-1H-imidazole-5-carboxylate(product 9b)

Using the procedure of Preparation 4, 0.2 g of ethyl1-[(4-boronophenyl)-methyl]-2-butyl-4-(methylthio)-1H-imidazole-5-carboxylateand 99 mg of ethylene glycol were reacted to obtain 0.21 g of theexpected product.

NMR: CDCl₃ (200 MHz) ppm 0.9 (t, 3H): CH₃ of nBu: 1.35 (m, 2H): CH₂ inposition 3 of nBu; 1.65 (m, 2H): CH₂ in position 2 of nBu; 2.63 (t, 2H):CH₂ in position 1 of nBu; 1.30 (t, 3H): CO₂ Et; 4.25 (q, 2H): CO₂ Et;2.63 (s, 3H): S--CH₃ ; 5.60 (s, 2H): Ar--CH₂ -imidazole; 4.45 (s, 4H):2CH₂ --O; 7.02 and 7.8 (2d); aromatics.

Preparation 10

2-bromo-N-[(propylamino)-carbonyl]-benzene-sulfonamide

15 g of 2-bromobenzene-sulfonamide in 150 ml of acetone were heated atreflux and 17.6 g of potassium carbonate were added. Then, 6.6 ml ofN-propylisocyanate were added, followed by stirring for 2 hours and 30minutes under reflux. The mixture was cooled to 0° C. and acidified topH 5 to obtain 18.35 g of the expected product melting at 218°-219° C.

NMR: CDCl₃ ppm 0.84 (t, 3H): CH₃ ; 1.45 (m, 2H), 3.07 (q, 2H): the CH₂'s; 6.08 (l, 1H): NH; 7.5 (m, 2H), 7.71 (dd, 1H), 8.25 (dd, 1H):aromatics; 10.00 (l, 1H): NH.

EXAMPLE 1

2-butyl-4H-(methylthio)-1-[[2'-((((propylamino)-carbonyl)-amino)-sulfonyl)-1,1'(biphenyl)-4-yl]-methyl]-1H-imidazole-5-carboxylicacid di-potassium salt

Stage A: 2-[(4-bromomethyl)-phenyl]-5,5-dimethyl-1,3,2-dioxaborolane

3.4 g of 4-methyl-phenyl-boronic acid (or its trimer form) and 2.6 g of2,2-dimethyl-propane-1,3-diol in 50 ml of cyclohexane were refluxed for4 hours while eliminating the water formed. 4.45 g of N-bromosuccinimideand 100 mg of azobisisobutyronitrile were added and the reaction mediumwas refluxed for 4 hours, cooled, filtered and washed with cyclohexaneto obtain 7 g of the desired product melting at 110° C.

NMR: CDCl₃ ppm 1.01 (s, 6H): (CH₃)₂ --C; 3.75 (s, 4H): CH₂ --O--B; 4.52(s, 2H): CH₂ Br; 6.95 (d, 2H), 7,72 (d, 2H): aromatics.

Stage B: ethyl2-butyl-1-[4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-benzyl]-4-(methylthio)-1H-imidazole-5-carboxylate

A mixture of -g of ethyl2-butyl-4-(methylthio)-1H-imidazole-5-carboxylate, 65 ml ofdimethylformamide and 3.75 g of potassium carbonate was stirred for 30minutes and then 8 g of the product of Stage A in solution in 32 ml ofdimethylformamide were added. The reaction mixture was stirred for 48hours at ambient temperature followed by pouring into water, extractingwith ethyl acetate, drying and evaporating to dryness under reducedpressure. After impasting in a mixture of cyclohexane--ethyl acetate(8-2), 5.67 g of the desired product melting at 145°-146° C. wereobtained.

NMR: CDCl₃ ppm 0.86 (t, 3H): CH₃ of nBu; 1.29 (t, 3H): CH₃ of CO₂ Et;1.34 (m, 2H), 1.62 (m, 2H), 2.60 (d, 2H): the CH₂ 's of nBu; 2.6 (s,3H): S--CH₃ ; 4.23 (q, 2H): CH₂ of CO₂ Et; 5.52 (s, 2H): benzyl CH₂ ;6.96 (d, 2H) and 7.71 (d, 2H): aromatics.

Stage C: ethyl2-butyl-4H-(methylthio)-1-[[2'((((propylamino)-carbonyl)-amino)-sulfonyl)-1,1'(biphenyl)-4-yl]-methyl]-1H-imidazole-5-carboxylate

A mixture of 62 mg of 2-bromoN-[(propylamino)-carbonyl]-benzene-sulfonamide, obtained by Preparation10, 4 ml of toluene, 0.193 ml of a 2N solution of sodium carbonate inwater, 7 mg of tetrakis (triphenylphosphine) palladium, 1.6 ml ofethanol and 85.5 mg of the product of Stage B and 0.4 ml of toluene wasstirred for 24 hours at reflux. A little toluene was added and thereaction medium was acidified to a pH of 2 with 2N hydrochloric acid.Extraction was carried out with methylene chloride, followed by washingwith water, drying and evaporating to dryness to obtain 165 mg ofproduct which was chromatographed on silica eluting with atoluene-dioxane-acetic acid mixture (95-4-1) to obtain 75 mg of thedesired product melting at 182° C.

NMR: CDCl₃ ppm 0.72 (t, 3H): CH₃ of nBu; 1.67 (m, 2H): CH₂ ; 3.03 (q,2H): CH₂ --NH; 6.01 (s, 1H): SO₂ NH; 6.11 (t, 1H): CONH; 7.25 (d), 7.64(t), 7.53 (t), 8.12 (d): aromatics.

Stage D:2-butyl-4H-(methylthio)-1-[[2'-((((propylamino)-carbonyl)-amino)-sulfonyl)-1,1'(biphenyl)-4-yl]-methyl]-1H-imidazole-5-carboxylicacid di-potassium salt

2.3 ml of a 6N solution of potassium hydroxide were added at 0° C. to asolution of 2 g of the product of Stage C in 40 ml of ethanol and thereaction medium was allowed to return to ambient temperature. After 72hours, the precipitate was separated and washed with 4 ml of ethanol,then with 4 ml of ethyl acetate. After drying, 2.04 g of the desiredproduct melting at >260° C. were obtained.

Analysis: C₂₆ H₃₀ K₂ N₄ O₅ S₂

    ______________________________________                                                   % C  % H        % N    % S                                         ______________________________________                                        calculated   50.30  4.8        9.02 10.33                                     found        50.5   4.9        9.0  10.3                                      ______________________________________                                    

EXAMPLE 2a

2-butyl-4H-(methylthio)-1-[[2'-((((propylamino)-carbonyl)-amino)-sulfonyl)-1,1'(biphenyl)-4-yl]-methyl]-1H-imidazole-5-carboxylicacid di-potassium salt

Stage A: 2-[(4-bromomethyl)-phenyl]-1,3,2-dioxaborolane

Using the procedure of Stage A of Example 1, 21.06 g of4-methyl-phenyl-boronic acid. 17.4 ml of trimethylene glycol, 250 ml ofcyclohexane, 440 mg of azabis isobutyronitrile and 32.03 g ofN-bromosuccinimide were reacted to obtain 31 g of the desired productmelting at 108°-109° C.

NMR (CDCl₃) ppm 2.05 (m, 2H): central CH₂ ; 4.14 (t, 4H): B--O--CH₂ ;4.49 (s, 2H): CH₂ --Br; 7.27 (d, 2H) and 7.74 (d, 2H): aromatics.

Stage B: ethyl2-butyl-1-[4-(1,3,2-dioxaborolan-2-yl)-benzyl]-4-(methylthio)-1H-imidazole-5-carboxylate

A mixture of 34.5 g of ethyl2-butyl-4-(methylthio)-1H-imidazole-5-carboxylate, 59 g of potassiumcarbonate, 3.82 g of tetrabutylammonium bromide and 312 ml of acetonewas stirred for 30 minutes at 20°-22° C. Then, 33.6 g of the product ofStage A were added and the reaction medium was stirred for 24 hours,filtered and concentrated to dryness under reduced pressure. Aftercrystallization both hot and cold from 59 ml of ethanol, 20.3 g of thedesired product melting at 120°-121° C. were obtained.

NMR (CDCl₃) ppm 0.86 (t, 3H): CH₃ ; 1.28 (t, 3H): CH₃ of CO₂ Et; 1.30(m, 2H): CH₂ ; 1.60 (m, 2H): CH₂ ; 2.58 (t, 2H): CH₂ --C═N; 2.5 (s, 3H):S--CH₃ ; 2.04 (m, 2H): central CH₂ ; 4.14 (t, 4H): BO--CH₂ ; 4.23 (t,2H): CH₂ of CO₂ Et; 5.52 (s, 2H): CH₂ --N: 6.94 (d, 2H) and 7.68 (d,2H): aromatics.

Stage C: ethyl2-butyl-4H-(methylthio)-1-[[2'((((propyl-amino)-carbonyl)-amino)-sulfonyl)-1,1'(biphenyl)-4-yl]-methyl]-1H-imidazole-5-carboxylate

12.9 mg of triphenylphosphine and 5.5 mg of palladium acetate were addedto a mixture of 264 mg of the product of Preparation 10 with 1.3 ml oftoluene, 1.027 ml of a 2N solution of sodium carbonate, 97.8 mg ofpotassium bromide and 17.3 mg of galvinoxyl which had been stirred for15 minutes. The mixture was stirred for 15 minutes and a solution of 400mg of the product of Stage B in 1.3 ml toluene and 5.3 ml of ethanol wasadded. The mixture was stirred for 24 hours at reflux. After dilutionwith toluene and acidification by the addition of 1.47 ml of 2Nhydrochloric acid, extraction was carried out with methylene chloride,followed by drying and evaporating to dryness under reduced pressure.The residue was chromatographed on silica (eluant:cyclohexane/n-chlorobutane/isopropanol 75-25-5) to obtain 0.25 g of thedesired product which was identical to the product of Stage C of Example1.

Stage D:2-butyl-4H-(methylthio)-1-[[2'((((propylamino)-carbonyl)-amino)-sulfonyl)-1,1'(biphenyl)-4-yl]-methyl]-1H-imidazole-5-carboxylicacid di-potassium salt

Using the procedure of Stage D of Example 1, the desired product wasobtained.

EXAMPLE 2b

2-butyl-4H-(methylthio)-1-[[2'-((((propylamino)-carbonyl)-amino)-sulfonyl)-1,1'(biphenyl)-4-yl]-methyl]-1H-imidazole-5-carboxylicacid di-potassium salt

Using the procedure of Example 2a, 10.1 mg of 1,3 bis-diphenylphosphinopropane was used in Stage C instead of 12.9 mg oftriphenylphosphine to obtain 49.6 mg of the product of Stage C ofExample 2a which was treated as indicated in Stage D of Example 1 toobtain the expected product.

EXAMPLE 3

ethyl2-butyl-4H-(methylthio)-1-[[2'-((((propylamino)-carbonyl)-amino)-sulfonyl)-1,1'(biphenyl)-4-yl]-methyl]-1H-imidazole-5-carboxylate

Using the procedure of Stage C of Example 1, 0.0824 g of2-iodo-N-propylamino-carbonyl-benzene-sulfonamide of Preparation 2 and109 mg of the product of Preparation 4 were reacted to obtain theexpected product.

EXAMPLE 4

ethyl2-butyl-4H-(methylthio)-1-[[2'-((((propylamino)-carbonyl)-amino)-sulfonyl)-1,1'-(biphenyl)-4-yl]-methyl]-1H-imidazole-5-carboxylate

Using the procedure of Stage C of Example 2, 828 mg of2-iodo-N-propylamino-carbonyl-sulfonamide and 1.2 g of the product ofPreparation 5 were reacted to obtain 905 mg of the desired product.

EXAMPLE 5

ethyl2-butyl-4H-(methylthio)-1-[[2'((((propylamino)-(sulfonyl)-1,1'(biphenyl)-4-yl]-methyl-1H-imidazole-5-carboxylate

Using the procedure of Stage C of Example 1, 442 mg of the product ofPreparation 6 and 264 mg of the product of Preparation 10 were reactedto obtain 152 mg of the desired product.

EXAMPLE 6

ethyl2-butyl-1H-(methylthio)-1-[[2'-((((propylamino)-carbonyl)-amino)-sulfonyl)-1,1'(biphenyl)-4-yl]-methyl]-1H-imidazole-5-carboxylate

Using the procedure of Stage C of Example 2, 1 g of the product ofPreparation 3 and 722 mg of the product of Preparation 10 were reactedto obtain 646 mg of the desired product.

EXAMPLE 7

ethyl2-butyl-4H-(methylthio)-1-[[2'-((((propylamino)-carbonyl)-amino)-sulfonyl)-1,1'(biphenyl)-4-yl]-methyl]1H-imidazole-5-carboxylate

Using the procedure of Example 6, 1 g of the product of Preparation 3and 828 mg of 2-iodo-N-[(propyl-amino)-carbonyl]-benzene-sulfonamide ofPreparation 2 were reacted to obtain 571 mg of the desired product.

EXAMPLE 8

ethyl2-butyl-4H-(methylthio)-[[2'-((((propylamino)-carbonyl)-amino)-sulfonyl)-1,1'(biphenyl)-4-yl]-methyl]-1H-imidazole-5-carboxylate

Using the procedure of Stage C of Example 2, 432.8 mg of the product ofPreparation 7 instead of the product of Stage B of Example 2 werereacted to obtain 121 mg of the expected product.

EXAMPLE 9

ethyl2-butyl-4H-(methylthio)-1-[[2'((((propylamino)-carbonyl)-amino)-sulfonyl)-1,1'(biphenyl)-4-yl-]-methyl]-1H-imidazole-5-carboxylate

Using the procedure of Stage C of Example 2, 387 mg of the product ofPreparation 9 instead of product of Stage B of Example 2 were reacted toobtain 220.5 mg of the expected product.

EXAMPLE 10

ethyl2-butyl-4H-(methylthio)-1-[[2'-((((propylamino)-carbonyl)-amino)-sulfonyl)-1,1'(biphenyl)-4-yl]-methyl]-1H-imidazole-5-carboxylate

Using the procedure of Stage C of Example 2, 440 mg of the product ofPreparation 8 instead of the product of Stage B of Example 2 werereacted to obtain 172 mg of the expected product.

EXAMPLE 11

Pharmaceutical Composition

Tablets were prepared containing 5 mg of the product of Example 1 andsufficient excipient of lactose, talc, starch, magnesium stearate for atablet of 200 mg.

There can be mentioned the following products which can be obtained bythe process as defined above which is a subject of the invention:##STR43## in which G preferably is --SO₂ --NH--CO--NH--CH₂ --CH₂ --CH₃or --SO₂ --NH--CO₂ alkyl in which alkyl preferably is methyl, ethyl,propyl or butyl.

Various modifications of the process of the invention may be madewithout departing from the spirit or scope thereof and it is to beunderstood that the invention is intended to be limited only as definedin the appended claims.

What is claimed is:
 1. A compound of the formula ##STR44## wherein R'₁ is selected from the group consisting of alkyl, alkenyl, alkynyl and alkylthio of up to 10 carbon atoms and cycloalkyl of 3 to 7 carbon atoms, all optionally substituted, R'₂ and R'₃ are individually selected from the group consisting of:a) hydrogen, halogen, --OH, --SH, acyl of an organic carboxylic acid of 1 to 7 carbon atoms, --CN, free, salified or esterified carboxy and --PO₃ (R)₂, b) --(CH₂)_(m1) --(SO)_(m2) --X--R₁₀, c) alkyl, alkenyl, alkoxy and optionally oxidized alkylthio of up to 6 carbon atoms optionally interrupted by at least one --O--, --S-- or nitrogen and optionally substituted, d) optionally substituted phenyl, benzoyl and optionally oxidized phenylthio, e) ##STR45## f) --S--S--R₁₂, R is hydrogen or optionally substituted alkyl or phenyl, m₁ is an integer from 0 to 4, m₂ is an integer from 0 to 2, X is selected from the group consisting of a single bond, --NH--, --NHCO--, --NH--COO--, --N═CH--N--R₁₃ and --NHCONH--, R₁₀ and R₁₃ are individually selected from the group consisting of hydrogen, alkyl and alkenyl of up to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, optionally substituted phenyl and benzyl, pyridyl, nitropyridyl, pyrimidyl, tetrazolyl, diazolyl, piperidinyl, alkylpiperidinyl, thiazolyl, alkylthiazolyl, tetrahydrofuranyl and methyltetrahydrofuranyl; R₆ and R₇ or R₈ and R₉ are individually selected from the group consisting of hydrogen, amino acids, optionally substituted alkyl and alkenyl of up to 6 carbon atoms, optionally substituted phenyl, benzyl and phenethyl and --(CH₂)_(m1) --S(O)_(m2) --X--R₁₀ or R₆ and R₇ or R₈ and R₉ taken together with the nitrogen to which they are attached form a monocyclic ring of 5 to 7 ring members or condensed rings of 8 to 14 ring members, both optionally containing at least one heteroatom of the group consisting of --O--, --S-- and nitrogen and optionally substituted with at least one member of the group consisting of halogen, --OH, --NO₂, alkyl and alkoxy of 1 to 6 carbon atoms, --NH₂, mono and dialkylamino of 1 to 6 carbon atoms and phenyl or R₈ and R₉ are individually acyl of an organic carboxylic acid of 1 to 6 carbon atoms or one of R₈ and R₉ is carbamoyl, alkoxycarbonyl or benzyloxycarbonyl or R₈ and R₉ together with the nitrogen form phthalimido or succinimido, R₁₂ has the definitions of R₂ and R₃ except for amino or alkoxy with the proviso at least one of R₂ and R₃ is an optionally substituted alkoxy or --(CH₂)_(m1) --S(O)_(m2) --X--R₁₀, B is boron and X₁ and X₂ are such that: either X₁ and X₂ are individually selected from the group consisting of hydroxyl, alkyl and alkoxy of 1 to 6 carbon atoms, phenyl and phenoxy, or X₁ with X₂ form with the boron atom to which they are linked a ring selected from the group consisting of ##STR46## X₃ is hydrogen or alkyl of 1 to 4 carbon atoms and X₄ is halogen, alkoxy, triflate or --O--SO₂ F with the reactive groups optionally protected.
 2. Novel intermediates of claim 1 selected from the group consisting ofethyl 1-[(4-boronophenyl)-methyl]-2-butyl-4-(methylthio)-1H-imidazole-5-carboxylate, ethyl 2-butyl-1-[4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-benzyl]-4-(methylthio)-1H-imidazole-5-carboxylate, ethyl 2-butyl-1-[4-(1,3,2-dioxaborolan-2-yl)-benzyl]-4-(methylthio)-1H-imidazole-5-carboxylate, ((4-((2-butyl-4-(methylthio)-5-(ethoxycarbonyl)-1H-imidazole-1-yl-(methyl)-phenyl)-((2,2'-(methylimino)-bis-((ethanolato))-(2-)-N,O,O')-boron, ethyl 2-butyl-1-(4-(1,3,2-benzodioxaborol-2-yl)-benzyl)-4-(methylthio)-1H-imidazole-5-carboxylate, ethyl 2-butyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxolaborolan-2-yl)-benzyl)-4-(methylthio)-1H-imidazole-5-carboxylate and ethyl 2-butyl-1-(4-(1,3,2-dioxolaborolan-2-yl)-benzyl)-4-(methylthio)-1H-imidazole-5-carboxylate. 